The design of an optimized chemical manufacturing process is very often a process as well, keeping in mind the goals of synthetic efficiency, waste reduction and use of materials having a reduced health risk. A manufacturing synthesis having a reduced environmental impact may employ a safer synthetic design by using minimally hazardous reagents and solvents, thus providing a new, more efficient and cost-effective process with positive environmental and economic impacts. The process of the present invention, while providing a pharmaceutically useful series of compounds, eliminates the use of known mutagenic reagents and chlorinated solvents. Accordingly, the synthesis of the present invention may reduce overall economic and environmental impact by using a reduced amount of reagents and solvents as well as less hazardous reagents and solvents, thereby reducing attendant disposal costs and the total cost of goods.
Patent Application CN2005-10023182 describes a method for producing quaternary ammonium salts by reacting trialkylamine with a halohydrocarbon at a molar ratio of 1:1 with linear or branched C10-22alkyl monohydric alcohols under a pressure of from 0 to 980 KPa(g) at a temperature of from 10 to 140° C. for a period of from 8 to 240 hours.
Patent Application EP0288857A3 describes quaternary ammonium halides prepared by the addition reaction of tertiary amines with alkyl halides in molar ratios of from 1:3 to 1:8 at a temperature of from 50 to 150° C. under elevated pressure in the absence of solvents.
U.S. Pat. No. 4,450,174 describes antimicrobial quaternary ammonium compounds, particularly decyl alkyl dimethylammonium chloride, prepared by the classical alkylation reaction of a tertiary amine with a primary alkyl halide, particularly didecyl methylamine with methylchloride gas.
U.S. Pat. No. 4,845,289 describes a process for the removal or reduction of residual trimethyl amine odor resulting from the quaternization of a halogen containing precursor with trimethyl amine by reacting the residual trimethyl amine with at least an equivalent amount of methyl chloride at a temperature of at least 50° C.
U.S. Pat. No. 6,444,846 describes a process for preparing a tetraalkyl ammonium halide using a catalytic amount of acetonitrile in a reaction under pressure and at an elevated temperature of an alkyl halide and a trialkyl amine and in which tetrafluoroborate can be subsequently prepared.
United States Patent Publication 2006/0293379, incorporated herein by reference in its entirety and for all purposes, describes CCR2 antagonist compounds of Formula (I) that may be prepared using the process of the present invention. Additionally, all other documents cited herein are incorporated by reference in their entirety and for all purposes.
The compound of Formula (Ia) has also been disclosed in U.S. Patent Publication 2006/0293379 and referred to as [4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride Compound 17 and synthesized as disclosed in Example 1 of same.